Previous work in our group has demonstrated that mouse salivary gland has the highest concentration of salivary derived VEGF protein when compared with other organs and is essential for normal palatal mucosal wound healing. We hypothesize that salivary-derived VEGF may also play a role in the gastrointestinal adaptation response. We examined the effect of submandibular sialoadenectomy (SAL), orogastric supplementation (OG) of VEGF and/or EGF on adaptation after small bowel resection (SBR). C57BL/6 Female mice underwent a 50% proximal SBR, SAL+SBR, SAL+SBR+EGFand/or VEGF or selective removal of the VEGF from the saliva using an Ad VEGF-Trap+SBR. Adaptation was evaluated in the remnant ileum after 3 days by ileal villus height (VH) and crypt depth (CD).The microvascular response was evaluated by CD31 immunostaining for sub-mucosal vessel density and for villus-vessel area ratio by FITC labeled von Willebrand Factor (vWF) immunostaining. The adaptive response after SBR was significantly attenuated in the SAL group in terms of VH (310±19.35vs250.4±8.816, p=0.01) and CD (120.541±2.82vs100.021±4.025, p=0.01). This response was partially corrected by OG VEGF or EGF alone. The adaptive response was completely restored when both were administered together suggesting that salivary VEGF and EGF both contribute to intestinal adaptation. VEGF increases the vascular density (6.4±0.29vs6.1±0.29vs5.96±0.20) and villus-vessel area ratio (0.713±0.01vs0.73±0.01) in the adapting bowel. Supplementation of both EGF and VEGF fully rescues adaptation suggesting that the adaptive response may be dependent upon VEGF driven angiogenesis. These results support a previously unrecognized role for VEGF in the small bowel adaptive response.